# Role of the ATP-dependent chromatin-remodeling enzyme Brg1 in the regulation of cardiac Na+ channel

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2022 · $57,890

## Abstract

NaV1.5, encoded by SCN5A gene, is a main α subunit of the cardiac Na+ channel. Na+ channel activity
determines cardiac excitability and electrical conduction. Decreased Na+ channel activity induced by suppression
of NaV1.5 expression is linked to ventricular tachycardia and fibrillation (VT/VF) in ischemic heart disease (IHD),
but the mechanisms of the NaV1.5 downregulation are largely unknown. Chromatin remodeling by Brahma-
related gene-1 (BRG1), a central catalytic subunit of numerous chromatin-modifying enzymatic complexes, play
an essential role in cardiac development and dysfunction by reprogramming gene expression under
pathophysiological conditions. BRG1 remodels chromatin activity and facilitates a subset of genes via interaction
with sequence-specific transcription factors. Our preliminary results showed that 1. NaV1.5 expression is
decreased in human hearts with IHD and mouse hearts with myocardial infarction (MI), 2. Na+ channel activity
is decreased in the peri-infarct zone (PIZ) of mouse MI hearts, 3. BRG1 is increased with BRG1 and β-catenin
nuclear accumulation of cardiomyocytes in human IHD and PIZ of mouse MI hearts, 4. Reactive oxygen species
(ROS) elevated in IHD increases BRG1 expression and decreases NaV1.5 expression by enhancing β-
catenin/TCF4 signaling, 5. A complex of BRG1/β-catenin/TCF4 complex recruited in TCF4 binding site inhibits
SCN5A promoter in HL-cells and suppresses NaV1.5 expression and Na+ channel activity, 6. BRG1 was detected
in the nuclei of adult cardiomyocytes; however, cardiac-specific knockout (KO) of BRG1 did not affect NaV1.5
expression and Na+ channel activity. Interestingly, enhanced β-catenin/TCF4 by cardiac-specific deletion of β-
catenin exon 3 (β-cat∆E3) suppressed NaV1.5 expression and Na+ channel activity, leading to susceptibility to
VT in mice challenging with flecainide (Ic antiarrhythmic drug) which was prevented by BRG1 KO.
Immunoprecipitation showed BRG1 interacts with β-cat∆E3 rather than β-catenin in adult cardiomyocytes,
suggesting BRG1 suppressing NaV1.5 expression is dependent on the enhanced β-catenin/TCF4 signaling.
These preliminary findings support our hypothesis that BRG1 interacts with β-catenin to promote β-catenin/TCF4
signaling-mediated suppression of NaV1.5, leading to deceleration of cardiac depolarization and development of
VT/VF in IHD. We will test this hypothesis in 2 specific aims, AIM 1: To determine whether increased BRG1
is necessary for enhanced β-catenin/TCF4 signaling-mediated suppression of NaV1.5 expression,
leading to decreased Na+ channel activity in moue MI hearts; AIM 2: To determine whether BRG1
suppressing NaV1.5 expression and Na+ channel activity by inhibiting SCN5A promoter activity through
β-catenin/TCF4. In order to achieve these 2 specific AIMs, we will use transgenic mice with cardiac BRG1 KO,
β-cat∆E3, BRG1 KO/β-cat∆E3 and TCF4 KO, BRG1 OE, and BRG1 OE/TCF4 KO in combination of MI
procedure and in vitro studies to determine whether BRG1 facili...

## Key facts

- **NIH application ID:** 10705353
- **Project number:** 1R56HL156980-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Haodong Xu
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $57,890
- **Award type:** 1
- **Project period:** 2022-09-22 → 2023-02-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705353

## Citation

> US National Institutes of Health, RePORTER application 10705353, Role of the ATP-dependent chromatin-remodeling enzyme Brg1 in the regulation of cardiac Na+ channel (1R56HL156980-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10705353. Licensed CC0.

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